ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4643C>T (p.Thr1548Met) (rs273900737)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203649 SCV000076629 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1548 of the BRCA1 protein (p.Thr1548Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 55249). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130001 SCV000184826 likely benign Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
GeneDx RCV000505759 SCV000210181 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4643C>T at the cDNA level, p.Thr1548Met (T1548M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature this variant would be defined as BRCA1 4762C>T. BRCA1 Thr1548Met has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1548Met occurs at a position that is not conserved and is located in a region of interaction with multiple proteins (Cantor 2001, Yarden 1999). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on the currently available information, we consider BRCA1 Thr1548Met to be a variant of uncertain significance.
Counsyl RCV000112371 SCV000488310 uncertain significance Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
Color RCV000130001 SCV000904984 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112371 SCV000145137 uncertain significance Breast-ovarian cancer, familial 1 2010-09-18 no assertion criteria provided clinical testing

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